P2‐377: A phase 2, double‐blind, placebo‐controlled study to evaluate the safety, tolerability, and effect on cognitive function of AL‐108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment

Abstract

Amnestic mild cognitive impairment (aMCI) is generally regarded as a prodromal form of AD based on recent studies that found neurofibrillary tangles (NFTs) in the brains of aMCI subjects and correlations between NFTs and memory loss. Testing of drugs that target NFTs therefore has relevance in the treatment of both aMCI and AD. Here, we report findings from a Phase 2 proof-of-concept clinical trial for the treatment of aMCI with AL-108. AL-108 is an intranasal formulation of an eight amino acid peptide, NAPVSIPQ, derived from the neuroprotective protein Activity-Dependent Neuroprotective Protein (ADNP). Preclinical experiments indicate that AL-108 has broad neuroprotective, neurotrophic, and cognitive protective properties across a range of disease models. AL-108 was previously shown to reduce both beta amyloid and tau phosphorylation in the triple transgenic mouse model of AD, hence affecting the pathology of NFTs. The trial was designed as a double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability and effect of two doses of AL-108 on cognitive function after 12 weeks of treatment. This study was open to men and women, age 55–85 years (inclusive) with Mini-Mental State Exam scores ≥24,self-reported memory complaint corroborated by spouse or companion, and Wechsler Memory Scale III (WMS-III) age-adjusted Logical Memory II score ≤ 5. Between March and September 2007, 144 subjects were randomized at 16 centers in the US. Cognitive tests consisting of digit span, Spielberger anxiety, spatial working memory, delayed match-to-sample, paired associates learning, and Stockings of Cambridge were conducted 4 weeks prior to drug administration (training), and then at baseline, 4, 8, 12, and 16 weeks. The primary endpoint is a change from baseline at Week 12 in a composite score that focuses on measures of memory. Secondary efficacy endpoints include analysis of the change in the individual cognitive tests as a function of both treatment and length of treatment. The last patient in this trial finished treatment in December 2007 and evaluations were completed in January 2008. At the time of presentation, details on the efficacy endpoints and results along with safety, tolerability and compliance will be discussed.